The present invention is generally in the field of prolonged release devices for delivery of pharmaceuticals where there is a critical need for uniform, zero-order release kinetics.
The field of drug delivery has developed over the last thirty years to the point where it is now possible to tailor delivery of the drugs with close precision, over prolonged periods of time, from weeks to months, following a single administration. Prolonged controlled release has been achieved using several different devices. Examples include mini-implantable pumps for a variety of drugs especially chemotherapeutics and highly potent neuroactive drugs, silicon tubing with release controlling pores in the ends for birth control agents, co-axial implants, transdermal patches and microencapsulated formulations. All have advantages and disadvantages. The mini-pump is extremely precise, but very expensive to manufacture. The mini-implantable pumps, silicon tubing and previously described co-axial implants all must be removed using an invasive procedure once the drug has been delivered. The microencapsulated formulations can be made using entirely biodegradable materials, but the release properties are not as controlled, and there can be an initial burst of drug. This is problematic for some drugs, which may have serious side effects if delivered in excess of the desired dosage, or which may be ineffective if not delivered in a sufficiently high dosage. Transdermal patches are only useful for the few drugs that will pass through the skin, and where precision of delivery is not mandatory.
Cancer is diagnosed in over one million Americans annually, and it is the cause of one in five deaths in the United States (approximately 1,400/day). Common progression of the disease often leads to chronic unrelieved pain. The use of narcotic analgesics including fentanyl and sufentanil are becoming more widely accepted as the treatment of choice. Because of the potential for developing tolerance as well as the toxic side effects, long-acting dosage forms that produce minimal initial burst are needed. As discussed above, several products including transdermal patches and implantable infusion systems are currently on the market. Transdermal patches can be used for outpatient treatment and have a duration of three days per dose. Intravenous infusion and intrathecal infusion deliver narcotics more consistently and can be used for longer periods of time. Currently approved infusion products generally use an externally-worn or implanted pump, are bulky, require surgical procedures to implant and to explant, and are very expensive systems. Duros® sufentanil, an osmotic pump designed for 100-day delivery of sufentanil, is currently undergoing clinical testing. This implant is much smaller and easier to administer, which provides advantages over the currently approved pumps, but requires removal at the end of the dosing period. This type of implant is described in WO 00/54745. A biodegradable implant could eliminate the need for removal thereby providing an added advantage to the patient, eliminating the cost and discomfort of the surgical explant procedure.
Implants that may be made of materials including biodegradable polymers have been described. For example, U.S. Pat. No. 4,666,704 to Shalati, et al., describes a controlled release implant, typically consisting of microparticle or pellets, that includes a core of a drug and water-insoluble drug and an outer polymeric membrane that can be formed by a coating of an organic solution of a water insoluble polymer and water soluble pore-forming agent. U.S. Patent application NO. 20020037309 to Jaworowicz, et al., describes an implant made of a polymer where the outer coating is annealed to decrease porosity and avoid burst release. Both of these require extensive processing steps, increasing cost, and may not be completely biodegradable.
It is therefore an object of the present invention to provide a controlled release device which is biodegradable, that releases over a prolonged period of time, and that provides very controlled zero-order release kinetics.
It is a further object of the present invention to provide a method of making such implants that is cost-effective, highly reproducible, and efficient.